Milk-alkali syndrome overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2]
Overview
Milk-alkali syndrome (also known as calcium-alkali syndrome) is characterized by a history of excessive calcium intake and hypercalcemia, metabolic alkalosis and varying degrees of renal insufficiency. In 1915, Bertram Sippy introduced a treatment for peptic ulcer disease which was an hourly mixture of milk and cream combined with alkaline powders. In 1923, the toxic effects of Sippy’s regimen were reported for the first time. With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome due to an increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention. Treatment of milk-alkali syndrome is mostly supportive and mainly includes the withdrawal of the offending agent, hydration, and intravenous volume expansion. Prognosis of milk-alkali syndrome is generally good and early diagnosis and treatment, with the withdrawal of the offending agent and supportive therapy, usually resolve the symptoms and abnormalities in milk-alkali syndrome (hypercalcemia, alkalosis and renal insufficiency).
Historical Perspective
In 1915, Bertram Sippy introduced a treatment for peptic ulcer disease which was an hourly mixture of milk and cream combined with alkaline powders.[1] In 1923, the toxic effects of Sippy’s regimen was reported for the first time.[2] With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome due to increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention.[3][4][5]
Classification
Milk-alkali syndrome may be classified as the following: acute (toxemic form), subacute (Cope's syndrome) and chronic (Burnett's syndrome).[6]
Pathophysiology
The exact pathogenesis of milk-alkali syndrome is unknown. Hypercalcemia in milk-alkali syndrome involves several mechanisms including: intestinal absorption of calcium is increased, bone buffering of calcium becomes saturated, and renal excretion of calcium is decreased.[5] Several factors that increase bicarbonate reabsorption and contribute to the alkalosis in milk-alkali syndrome include: volume depletion due to increased sodium and free water excretion caused by increased calcium intake, suppression of PTH, direct tubular effects of calcium and other factors that cause volume depletion or alkalosis such as vomiting or thiazide use.[7]
Causes
Currently, the main cause of milk-alkali syndrome is calcium carbonate consumption, mostly in postmenopausal women for osteoporosis prevention or treatment or in patients on glucocorticoid therapy (for example in organ transplantation), and chronic renal disease.[8] With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome mostly due to increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention.[3][4][5]
Differentiating Milk-alkali syndrome from other Diseases
Milk-alkali syndrome should be differentiated from other disorders that cause hypercalcemia such as hyperparathyroidism, malignancies, hyperthyroidism, immobilization, sarcoidosis and some drugs (thiazides, vitamin D, lithium and vitamin A toxicity)[9]
Risk Factors
Patients with the following conditions are more susceptible to milk-alkali syndrome: Older age, preexisting chronic renal disease, concurrent vomiting (bulimia nervosa or hyperemesis gravidarum ) and use of certain drugs like thiazide, NSAIDs, and ACE inhibitors.[3][10][11][12][5][13][4]
Screening
There is insufficient evidence to recommend routine screening for milk-alkali syndrome.
Natural History, Complications and Prognosis
Most patients with milk-alkali syndrome are asymptomatic and may be incidentally diagnosed. Complications of milk-alkali syndrome may include: confusion, psychosis, renal insufficiency, pancreatitis, abnormalities in cardiac conduction, and metastatic calcification. Prognosis of milk-alkali syndrome is generally good and early diagnosis and treatment, with withdrawal of the offending agent and supportive therapy, usually resolve the symptoms and abnormalities in milk-alkali syndrome (hypercalcemia, alkalosis and renal insufficiency).[9][8][3][14][15][3][8][16][17]
Epidemiology and Demographics
The exact incidence and prevalence of milk-alkali syndrome is not known.[18] With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome due to increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention.[3][4][5] Milk-alkali syndrome is the third most common cause of hypercalcemia in hospitalized patients after primary hyperparathyroidism and malignancies.[10]
Diagnosis
Diagnostic Study of Choice
Milk-alkali syndrome is diagnosed by a history of excessive calcium consumption, hypercalcemia, metabolic alkalosis and variable degrees of renal insufficiency. [3]
History and Symptoms
In patients with milk-alkali syndrome, there is a history of excessive calcium and absorbable alkali consumption.[3] Symptoms of milk-alkali syndrome may inculde: dizziness, vertigo, confusion, apathy, nausea, vomiting, anorexia, distaste for milk, headache, anorexia, pruritus, polydipsia, polyuria, myalgia, tremor, psychosis, and abnormal calcifications (keratopathy, renal calcinosis).[14][15]
Physical Examination
The following should be considered in the physical examination of milk-alkali syndrome: vertigo, confusion, apathy, nausea, vomiting, pruritus, polydipsia, polyuria, myalgia, tremor, psychosis, and abnormal calcifications (keratopathy, renal calcinosis).[14][15][3]
Laboratory Findings
The following laboratory findings are usually seen in milk-alkali syndrome: hypercalcemia, metabolic alkalosis, variable degrees of renal insufficiency, low or normal phosphorus, low Vitamin D, and low PTH.[8][3][19][4]
Electrocardiogram
Milk-alkali syndrome causes hypercalcemia and hypercalcemia may cause the following findings on electrocardiogram (ECG): shortened QT interval (the most common finding), shortened ST segment, PR prolongation, increased amplitude of QRS complex, decreased amplitude of T wave, T wave notching, transient ST segment elevation, bradycardia, sinus arrest, and ventricular arrhythmias.[20][21][22][23][24][25]
X-ray
X-ray is not useful in the diagnosis of milk-alkali syndrome. However, X-ray may be useful in excluding other causes of hypercalcemia. Renal calcium deposits are not seen on X-ray in milk-alkali syndrome.[3]
Echocardiography and Ultrasound
Echocardiography is not useful in the diagnosis of milk-alkali syndrome. Ultrasound is not useful in the diagnosis of milk-alkali syndrome. However, ultrasound may be helpful in excluding other causes of hypercalcemia.
CT Scan
CT scan is not useful in the diagnosis of milk-alkali syndrome. However, CT scan may be helpful in excluding other causes of hypercalcemia.
MRI
MRI is not useful in the diagnosis of milk-alkali syndrome. However, MRI may be helpful in excluding other causes of hypercalcemia.
Other Imaging Findings
There are no other imaging findings associated with milk-alkali syndrome.
Other Diagnostic studies
There are no other diagnostic studies associated with milk-alkali syndrome.
Treatment
Medical therapy
Treatment of milk-alkali syndrome is mostly supportive and mainly includes withdrawal of the offending agent, hydration and intravenous volume expansion. However, other treatments such as therapy with calcium supplements (in temporary hypocalcemia) and hemodialysis (in acute or chronic irreversible renal insufficiency) may be required.[8][3]
Surgery
Surgical intervention is not recommended for the routine management of milk-alkali syndrome.
Primary Prevention
Effective measures for the primary prevention of milk-alkali syndrome includes public education about the potential adverse effects of calcium supplements. Calcium intake less than 2 g/daily is usually safe, however, 1.2 to 1.5 g/daily of calcium intake should be taken by individuals with risk factors for milk-alkali syndrome.[3][10][11][12][5][13][4]
Secondary Prevention
There are no established measures for the secondary prevention of milk-alkali syndrome.
Cost-Effectiveness of Therapy
There is insufficient evidence about the cost-effectiveness of therapy in milk-alkali syndrome.
Future or Investigational Therapies
No further or investigational therapies have been suggested in milk-alkali syndrome.
References
- ↑ Sippy BW (1983). "Landmark article May 15, 1915: Gastric and duodenal ulcer. Medical cure by an efficient removal of gastric juice corrosion. By Bertram W. Sippy". JAMA. 250 (16): 2192–7. doi:10.1001/jama.250.16.2192. PMID 6352976.
- ↑ HARDT, LEO L. (1923-02-01). "TOXIC MANIFESTATIONS FOLLOWING THE ALKALINE TREATMENT OF PEPTIC ULCER". Archives of Internal Medicine. American Medical Association (AMA). 31 (2): 171. doi:10.1001/archinte.1923.00110140023003. ISSN 0003-9926.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 Medarov BI (2009). "Milk-alkali syndrome". Mayo Clin Proc. 84 (3): 261–7. doi:10.1016/S0025-6196(11)61144-0. PMC 2664604. PMID 19252114.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Arroyo M, Fenves AZ, Emmett M (2013). "The calcium-alkali syndrome". Proc (Bayl Univ Med Cent). 26 (2): 179–81. doi:10.1080/08998280.2013.11928954. PMC 3603742. PMID 23543983.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Felsenfeld AJ, Levine BS (2006). "Milk alkali syndrome and the dynamics of calcium homeostasis". Clin J Am Soc Nephrol. 1 (4): 641–54. doi:10.2215/CJN.01451005. PMID 17699269.
- ↑ McMillan DE, Freeman RB (1965). "The milk alkali syndrome: a study of the acute disorder with comments on the development of the chronic condition". Medicine (Baltimore). 44 (6): 485–501. doi:10.1097/00005792-196511000-00002. PMID 5851468.
- ↑ Fiorino AS (1996). "Hypercalcemia and alkalosis due to the milk-alkali syndrome: a case report and review". Yale J Biol Med. 69 (6): 517–23. PMC 2589043. PMID 9436295.
- ↑ 8.0 8.1 8.2 8.3 8.4 Beall DP, Henslee HB, Webb HR, Scofield RH (2006). "Milk-alkali syndrome: a historical review and description of the modern version of the syndrome". Am. J. Med. Sci. 331 (5): 233–42. PMID 16702792. Unknown parameter
|month=ignored (help) - ↑ 9.0 9.1 Ali, Rimsha; Patel, Chinmay (2020-05-30). "Milk-Alkali Syndrome". NCBI Bookshelf. PMID 32491432 Check
|pmid=value (help). Retrieved 2020-07-14. - ↑ 10.0 10.1 10.2 Beall DP, Scofield RH (1995). "Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia". Medicine (Baltimore). 74 (2): 89–96. doi:10.1097/00005792-199503000-00004. PMID 7891547.
- ↑ 11.0 11.1 Whiting SJ, Wood R, Kim K (1997). "Calcium supplementation". J Am Acad Nurse Pract. 9 (4): 187–92. PMID 9274239.
- ↑ 12.0 12.1 Patel AM, Goldfarb S (2010). "Got calcium? Welcome to the calcium-alkali syndrome". J Am Soc Nephrol. 21 (9): 1440–3. doi:10.1681/ASN.2010030255. PMID 20413609.
- ↑ 13.0 13.1 Picolos MK, Lavis VR, Orlander PR (2005). "Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients". Clin Endocrinol (Oxf). 63 (5): 566–76. doi:10.1111/j.1365-2265.2005.02383.x. PMID 16268810.
- ↑ 14.0 14.1 14.2 Orwoll ES (1982). "The milk-alkali syndrome: current concepts". Ann Intern Med. 97 (2): 242–8. doi:10.7326/0003-4819-97-2-242. PMID 7049033.
- ↑ 15.0 15.1 15.2 Texter EC, Laureta HC (1966). "The milk-alkali syndrome". Am J Dig Dis. 11 (5): 413–8. doi:10.1007/BF02233637. PMID 5327389.
- ↑ George S, Clark JD (2000). "Milk alkali syndrome-an unusual syndrome causing an unusual complication". Postgrad Med J. 76 (897): 422–3. doi:10.1136/pmj.76.897.422. PMC 1741646. PMID 10878206.
- ↑ Jenkins JK, Best TR, Nicks SA, Murphy FY, Bussell KL, Vesely DL (1987). "Milk-alkali syndrome with a serum calcium level of 22 mg/dl and J waves on the ECG". South Med J. 80 (11): 1444–9. doi:10.1097/00007611-198711000-00028. PMID 3686151.
- ↑ Patel AM, Adeseun GA, Goldfarb S (2013). "Calcium-alkali syndrome in the modern era". Nutrients. 5 (12): 4880–93. doi:10.3390/nu5124880. PMC 3875933. PMID 24288027.
- ↑ Kapsner P, Langsdorf L, Marcus R, Kraemer FB, Hoffman AR (1986). "Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation". Arch Intern Med. 146 (10): 1965–8. PMID 3532984.
- ↑ Wesson LC, Suresh V, Parry RG (2009). "Severe hypercalcaemia mimicking acute myocardial infarction". Clin Med (Lond). 9 (2): 186–7. doi:10.7861/clinmedicine.9-2-186. PMC 4952678. PMID 19435131.
- ↑ Ahmed R, Hashiba K (1988). "Reliability of QT intervals as indicators of clinical hypercalcemia". Clin Cardiol. 11 (6): 395–400. doi:10.1002/clc.4960110607. PMID 2899466.
- ↑ Schutt RC, Bibawy J, Elnemr M, Lehnert AL, Putney D, Thomas AS; et al. (2014). "Case report: Severe hypercalcemia mimicking ST-segment elevation myocardial infarction". Methodist Debakey Cardiovasc J. 10 (3): 193–7. doi:10.14797/mdcj-10-3-193. PMC 4280246. PMID 25574349.
- ↑ Otero J, Lenihan DJ (2000). "The "normothermic" Osborn wave induced by severe hypercalcemia". Tex Heart Inst J. 27 (3): 316–7. PMC 101092. PMID 11093425.
- ↑ Kiewiet RM, Ponssen HH, Janssens EN, Fels PW (2004). "Ventricular fibrillation in hypercalcaemic crisis due to primary hyperparathyroidism". Neth J Med. 62 (3): 94–6. PMID 15209475.
- ↑ Kelwade JV, Modi KD, Kumar N, Parekh H (2016). "Hypercalcemia and electrocardiogram changes". Indian J Endocrinol Metab. 20 (6): 892–893. doi:10.4103/2230-8210.192900. PMC 5105587. PMID 27867906.